View source for Toremifene

{{Short description|Chemical compound}}
{{Drugbox
| verifiedrevid = 470611877
| IUPAC_name = 2-[4-[(1''Z'')-4-Chloro-1,2-diphenyl-but-1-en-1-yl]phenoxy]-''N'',''N''-dimethylethanamine
| image = Toremifene.svg
| width = 250px
| image2 = Toremifene molecule ball.png
| width2 = 250px

<!--Clinical data-->
| pronounce = {{IPAc-en|ˈ|t|ɔːr|ə|m|ɪ|f|iː|n}}
| tradename = Fareston, others
| Drugs.com = {{drugs.com|monograph|fareston}}
| MedlinePlus = a608003
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category =
| licence_EU = yes
| legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->
| legal_UK = <!-- GSL / P / POM / CD -->
| legal_US = <!-- OTC / Rx-only -->
| legal_status =
| routes_of_administration = [[Oral administration|By mouth]]
| class = [[Selective estrogen receptor modulator]]

<!--Pharmacokinetic data-->
| bioavailability = Good/~100%<ref name="pmid11108432" /><ref name="Jr.Lawrence2015">{{cite book| vauthors = DeVita Jr VT, Lawrence TS, Rosenberg SA |title=DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology|url=https://books.google.com/books?id=HEAYBgAAQBAJ&pg=PT1126|date=7 January 2015|publisher=Wolters Kluwer Health|isbn=978-1-4698-9455-3|pages=1126–}}</ref>
| protein_bound = 99.7%<ref name="pmid11108432" />
| metabolism = [[Liver]] ([[CYP3A4]])<ref name="RosenthalBurchum2017" /><ref name="Jr.Lawrence2015" />
| metabolites = N-Desmethyltoremifene; 4-Hydroxytoremifene; [[Ospemifene]]<ref name="ChabnerLongo2011" /><ref name="Toremifene-Label"/>
| elimination_half-life = Toremifene: 3–7 days<ref name="pmid11108432" /><br />Metabolites: 4–21 days<ref name="Jr.Lawrence2015" /><ref name="Toremifene-Label"/><ref name="pmid11108432" />
| excretion = [[Feces]]: 70% (as metabolites)<ref name="Jr.Lawrence2015" />

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 89778-26-7
| CAS_supplemental = <br />89778-27-8 ([[citrate]])
| ATC_prefix = L02
| ATC_suffix = BA02
| ATC_supplemental =
| PubChem = 3005573
| IUPHAR_ligand = 4325
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00539
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2275722
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 7NFE54O27T
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08620
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 9635
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1655
| PDB_ligand = T0R
| synonyms = (''Z'')-Toremifene; 4-Chlorotamoxifen; 4-CT; Acapodene; CCRIS-8745; FC-1157; FC-1157a; GTx-006; NK-622; NSC-613680

<!--Chemical data-->
| C=26 | H=28 | Cl=1 | N=1 | O=1
| SMILES = ClCCC(/c1ccccc1)=C(/c2ccc(OCCN(C)C)cc2)c3ccccc3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C26H28ClNO/c1-28(2)19-20-29-24-15-13-23(14-16-24)26(22-11-7-4-8-12-22)25(17-18-27)21-9-5-3-6-10-21/h3-16H,17-20H2,1-2H3/b26-25-
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = XFCLJVABOIYOMF-QPLCGJKRSA-N
}}
<!-- Definition and medical uses -->
'''Toremifene''', sold under the brand name '''Fareston''' among others, is a medication which is used in the treatment of [[metastatic breast cancer|advanced breast cancer]] in [[menopause|postmenopausal]] women.<ref name="Toremifene-Label">{{cite web | title = FARESTON (toremifene citrate) 60 mg Tablets oral administration | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020497s006lbl.pdf | archive-url = https://web.archive.org/web/20170118192002/http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020497s006lbl.pdf | url-status = dead | archive-date = January 18, 2017 | work = GTx, Inc. | publisher = U.S. Food and Drug Administration | date = March 2011 }}</ref><ref name="MillerIngle2002">{{cite book| vauthors = Miller WR, Ingle JN |title=Endocrine Therapy in Breast Cancer|url=https://books.google.com/books?id=00_LBQAAQBAJ&pg=PA55|date=8 March 2002|publisher=CRC Press|isbn=978-0-203-90983-6|pages=55–57}}</ref><ref name="ChabnerLongo2011">{{cite book| vauthors = Chabner BA, Longo DL |title=Cancer Chemotherapy and Biotherapy: Principles and Practice|url=https://books.google.com/books?id=0U4aj4GZWCIC&pg=PA659|date=7 December 2011|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-4820-6|pages=659–}}</ref> It is taken [[oral administration|by mouth]].<ref name="Toremifene-Label" />

<!-- Side effects -->
[[Side effect]]s of toremifene include [[hot flash]]es, [[sweating]], [[nausea]], [[vomiting]], [[dizziness]], [[vaginal discharge]], and [[vaginal bleeding]].<ref name="RosenthalBurchum2017" /><ref name="SchiffArrillaga2017" /> It can also cause [[blood clot]]s, [[heart dysrhythmia|irregular heartbeat]], [[cataract]]s, [[visual disturbance]]s, [[elevated liver enzymes]], [[endometrial hyperplasia]], and [[endometrial cancer]].<ref name="RosenthalBurchum2017" /> [[Hypercalcemia|High blood calcium levels]] can occur in women with [[bone metastasis|bone metastases]].<ref name="RosenthalBurchum2017" />

<!-- Mechanism of action -->
The medication is a [[selective estrogen receptor modulator]] (SERM) and hence is a mixed [[agonist]]–[[receptor antagonist|antagonist]] of the [[estrogen receptor]] (ER), the [[biological target]] of [[estrogen]]s like [[estradiol]].<ref name="RosenthalBurchum2017" /><ref name="SchiffArrillaga2017" /> It has [[estrogen (medication)|estrogen]]ic effects in [[bone]], the [[liver]], and the [[uterus]] and [[antiestrogen]]ic effects in the [[breast]]s.<ref name="MillerIngle2002" /><ref name="MorrowJordan2003" /><ref name="ScholarlyEditions2013" /><ref name="RosenthalBurchum2017" /> It is a [[triphenylethylene]] [[chemical derivative|derivative]] and is closely related to [[tamoxifen]].<ref name="CanoAlsina2006" />

<!-- History, society, and culture -->
Toremifene was introduced for medical use in 1997.<ref name="SilvaZurrida2005" /><ref name="BidlackOmaye2000" /> It was the first [[antiestrogen]] to be introduced since tamoxifen in 1978.<ref name="DiSaiaCreasman2017" /> It is available as a [[generic drug|generic medication]] in the [[United States]].<ref name="Drugs.com-Generic">{{Cite news|url=https://www.drugs.com/availability/generic-fareston.html|title=Generic Fareston Availability - Drugs.com|work=Drugs.com|access-date=2019-04-19|language=en-US}}</ref>

{{TOC limit|3}}

==Medical uses==
Toremifene is approved for the treatment of [[metastatic breast cancer]] in postmenopausal women with [[hormone receptor positive breast tumor|estrogen receptor-positive]] or unknown-status [[tumor]]s.<ref name="Toremifene-Label" /><ref name="MillerIngle2002" /> This is its only approved use in the [[United States]].<ref name="Toremifene-Label"/> It shows equivalent effectiveness to tamoxifen for this indication.<ref name="MillerIngle2002" /><ref name="pmid18062751" /> Toremifene has been found to be effective in the treatment of [[mastalgia|breast pain]] and may be a more effective medication than tamoxifen for this indication.<ref name="BlandCopeland2017">{{cite book| vauthors = Bland KI, Copeland EM, Klimberg VS, Gradishar WJ |title=The Breast E-Book: Comprehensive Management of Benign and Malignant Diseases|url=https://books.google.com/books?id=hJwqDwAAQBAJ&pg=PA86|date=29 June 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-51187-2|pages=86–}}</ref> It also has superior effects on [[bone mineral density]] and [[lipid profile]], including levels of [[cholesterol]] and [[triglyceride]]s, compared to tamoxifen.<ref name="pmid18062751" /> Toremifene has been reported to significantly improve symptoms of [[gynecomastia]] in men.<ref name="TabbalFuleihan2010">{{cite book| vauthors = Tabbal M, Fuleihan GE |title=Osteoporosis in Men |chapter=Future Therapies|year=2010|pages=713–732|doi=10.1016/B978-0-12-374602-3.00057-2|isbn=9780123746023}}</ref>

===Available forms===
Toremifene is provided in the form of 60&nbsp;mg [[oral administration|oral]] [[tablet (pharmacy)|tablet]]s.<ref name="CNE2019">{{cite book| vauthors = Wirfs MJ |title=The APRN and PA's Complete Guide to Prescribing Drug Therapy 2020|url=https://books.google.com/books?id=6DiPDwAAQBAJ&pg=PA60|date=9 May 2019|publisher=Springer Publishing Company|isbn=978-0-8261-7934-0|pages=60–}}</ref><ref name="CasciatoTerrito2012">{{cite book | vauthors = Casciato DA | chapter = Chapter 4: Cancer Chemotherapeutic Agents | veditors = Casciato DA, Territo MC |title=Manual of Clinical Oncology|chapter-url=https://books.google.com/books?id=4ggoPDgZx2YC&pg=PA122|year=2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-1560-4|pages=122–}}</ref>

==Side effects==
The [[side effect]]s of toremifene are similar to those of tamoxifen.<ref name="RosenthalBurchum2017" /> The most common side effect is [[hot flash]]es.<ref name="RosenthalBurchum2017" /> Other side effects include [[sweating]], [[nausea]], [[vomiting]], [[dizziness]], [[vaginal discharge]], and [[vaginal bleeding]].<ref name="RosenthalBurchum2017" /><ref name="SchiffArrillaga2017">{{cite book| vauthors = Schiff D, Arrillaga I, Wen PY |title=Cancer Neurology in Clinical Practice: Neurological Complications of Cancer and its Treatment|url=https://books.google.com/books?id=wQI2DwAAQBAJ&pg=PA296|date=16 September 2017|publisher=Humana Press|isbn=978-3-319-57901-6|pages=296–}}</ref> In women with [[bone metastasis|bone metastases]], [[hypercalcemia]] may occur.<ref name="RosenthalBurchum2017" /> Toremifene has a small risk of [[thromboembolism|thromboembolic event]]s.<ref name="RosenthalBurchum2017" /> [[Cataract]]s, [[visual impairment|vision changes]], and [[elevated transaminases|elevation of liver enzymes]] have been reported.<ref name="RosenthalBurchum2017" /><ref name="SchiffArrillaga2017" /> The drug [[drug-induced QT prolongation|prolongs the QT interval]] and hence has a risk of potentially fatal [[Heart arrhythmia|dysrhythmia]]s.<ref name="RosenthalBurchum2017" /> The risk of dysrhythmias can be reduced by avoiding use in patients with [[hypokalemia]], [[hypomagnesemia]], pre-existing QT prolongation, and in those taking other QT-prolonging drugs.<ref name="RosenthalBurchum2017" /> Because toremifene has [[estrogen (medication)|estrogen]]ic actions in the [[uterus]], it can increase the risk of [[endometrial hyperplasia]] and [[endometrial cancer]].<ref name="RosenthalBurchum2017" />

Toremifene appears to be safer than tamoxifen.<ref name="pmid18062751" /> It has a lower risk of [[venous thromboembolism]] (VTE) (e.g., [[pulmonary embolism]]), [[stroke]], and [[cataract]]s.<ref name="pmid18062751" /> The lower risk of VTE may be related to the fact tamoxifen decreases levels of the [[antithrombin III]] to a significantly greater extent than either 60 or 200&nbsp;mg/day toremifene.<ref name="pmid18062751" />

==Interactions==
Toremifene is a [[substrate (biochemistry)|substrate]] of [[CYP3A4]], a [[cytochrome P450]] [[enzyme]], and hence drugs that [[enzyme inducer|induce]] or [[enzyme inhibitor|inhibit]] this enzyme can respectively decrease or increase levels of toremifene in the body.<ref name="RosenthalBurchum2017" />

==Pharmacology==

===Pharmacodynamics===
Toremifene is a [[selective estrogen receptor modulator]] (SERM).<ref name="RosenthalBurchum2017" /><ref name="SchiffArrillaga2017" /><ref name="pmid16503765">{{cite journal | vauthors = Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA | title = Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy | journal = Expert Opin Investig Drugs | volume = 15 | issue = 3 | pages = 293–305 | date = March 2006 | pmid = 16503765 | doi = 10.1517/13543784.15.3.293 | s2cid = 29510508 }}</ref> That is, it is a [[binding selectivity|selective]] mixed [[agonist–antagonist]] of the [[estrogen receptor]]s (ERs), with [[estrogen (medication)|estrogen]]ic actions in some [[tissue (biology)|tissue]]s and [[antiestrogen]]ic actions in other tissues.<ref name="RosenthalBurchum2017" /><ref name="SchiffArrillaga2017" /> The medication has estrogenic effects in [[bone]], [[partial agonist|partial]] estrogenic effects in the [[uterus]] and [[liver]], and antiestrogenic effects in the [[breast]]s.<ref name="MillerIngle2002" /><ref name="MorrowJordan2003">{{cite book| vauthors = Morrow M, Jordan VC |title=Managing Breast Cancer Risk|url=https://books.google.com/books?id=HXKibhaF5lMC&pg=PA192|year=2003|publisher=PMPH-USA|isbn=978-1-55009-260-8|pages=192–}}</ref><ref name="ScholarlyEditions2013">{{cite book|title=Selective Estrogen Receptor Modulators—Advances in Research and Application: 2013 Edition: ScholarlyBrief|url=https://books.google.com/books?id=AAzZGOf6rl0C&pg=PT51|date=1 May 2013|publisher=ScholarlyEditions|isbn=978-1-4901-0447-8|pages=51–}}</ref><ref name="RosenthalBurchum2017">{{cite book| vauthors = Rosenthal L, Burchum J |title=Lehne's Pharmacotherapeutics for Advanced Practice Providers - E-Book|url=https://books.google.com/books?id=gfYoDgAAQBAJ&pg=PA931|date=17 February 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-44779-9|pages=931–}}</ref>

{{Tissue-specific estrogenic and antiestrogenic activity of SERMs}}

The [[affinity (pharmacology)|affinity]] of toremifene for the ER is similar to that of tamoxifen.<ref name="MillerIngle2002" /><ref name="Workman2012">{{cite book| vauthors = Workman P |title=New Approaches in Cancer Pharmacology: Drug Design and Development|url=https://books.google.com/books?id=ZLkJCAAAQBAJ&pg=PT104|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-77874-2|pages=104–}}</ref><ref name="pmid2941176">{{cite journal | vauthors = Kallio S, Kangas L, Blanco G, Johansson R, Karjalainen A, Perilä M, Pippo I, Sundquist H, Södervall M, Toivola R | title = A new triphenylethylene compound, Fc-1157a. I. Hormonal effects | journal = Cancer Chemother Pharmacol | volume = 17 | issue = 2 | pages = 103–8 | date = 1986 | pmid = 2941176 | doi = 10.1007/BF00306736 | s2cid = 13238715 }}</ref> In studies using rat ER, toremifene had about 1.4% and tamoxifen had about 1.6% of the affinity of [[estradiol (medication)|estradiol]] for the ER.<ref name="WittliffKerr2005">{{cite book | vauthors = Wittliff JL, Kerr II JL, Andres SA  | year = 2005 | chapter = Estrogens IV: Estrogen-Like Pharmaceuticals | veditors = Wexler P | title = Encyclopedia of Toxicology, 2nd Edition | volume = Dib-L | pages = 254–258 | publisher = Elsevier | isbn = 9780080548005 | chapter-url = https://books.google.com/books?id=dEnbcGW44RYC&pg=PT3318}}</ref><ref name="pmid10746941">{{cite journal | vauthors = Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL, Tong W, Shi L, Perkins R, Sheehan DM | title = The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands | journal = Toxicol Sci | volume = 54 | issue = 1 | pages = 138–53 | date = March 2000 | pmid = 10746941 | doi = 10.1093/toxsci/54.1.138 | doi-access = free }}</ref><ref name="pmid11258977">{{cite journal | vauthors = Fang H, Tong W, Shi LM, Blair R, Perkins R, Branham W, Hass BS, Xie Q, Dial SL, Moland CL, Sheehan DM | title = Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens | journal = Chem Res Toxicol | volume = 14 | issue = 3 | pages = 280–94 | date = March 2001 | pmid = 11258977 | doi = 10.1021/tx000208y }}</ref><ref name="pmid8142059">{{cite journal | vauthors = Chander SK, Sahota SS, Evans TR, Luqmani YA | title = The biological evaluation of novel antioestrogens for the treatment of breast cancer | journal = Crit Rev Oncol Hematol | volume = 15 | issue = 3 | pages = 243–69 | date = December 1993 | pmid = 8142059 | doi = 10.1016/1040-8428(93)90044-5 }}</ref><ref name="KavlockDaston2012">{{cite book| vauthors = Kavlock RJ, Daston GP |title=Drug Toxicity in Embryonic Development II: Advances in Understanding Mechanisms of Birth Defects: Mechanistics Understanding of Human Development Toxicants|url=https://books.google.com/books?id=vcHsCAAAQBAJ&pg=PA437|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60447-8|pages=437–}}</ref><ref name="pmid2941176" /> The affinities (K<sub>i</sub>) of toremifene at the human ERs have been reported as 20.3 ± 0.1&nbsp;nM for the [[ERα]] and 15.4 ± 3.1&nbsp;nM for the [[ERβ]].<ref name="pmid16503765" /> In other rat ER studies, toremifene had 3–9% of the affinity of estradiol for the ER while its [[metabolite]]s ''N''-desmethyltoremifene and 4-hydroxytoremifene had 3–5% and 64–158% of the affinity of estradiol for the ER, respectively.<ref name="pmid2147128">{{cite journal | vauthors = Kangas L | title = Biochemical and pharmacological effects of toremifene metabolites | journal = Cancer Chemother Pharmacol | volume = 27 | issue = 1 | pages = 8–12 | date = 1990 | pmid = 2147128 | doi = 10.1007/BF00689269 | s2cid = 11502291 }}</ref><ref name="pmid2149286">{{cite journal | vauthors = Robinson SP, Parker CJ, Jordan VC | title = Preclinical studies with toremifene as an antitumor agent | journal = Breast Cancer Res Treat | volume = 16 | issue = Suppl | pages = S9–17 | date = August 1990 | pmid = 2149286 | doi = 10.1007/BF01807139 | s2cid = 19989845 }}</ref><ref name="Osborne2012">{{cite book| vauthors = Osborne CK |title=Endocrine Therapies in Breast and Prostate Cancer|url=https://books.google.com/books?id=gW0eBAAAQBAJ&pg=PA104|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4613-1731-9|pages=104–}}</ref> The affinity of another metabolite, 4-hydroxy-''N''-desmethyltoremifene, was not assessed.<ref name="pmid2149286" /> 4-Hydroxytoremifene showed about 100-fold higher antiestrogenic [[potency (pharmacology)|potency]] than toremifene ''[[in vitro]]'' in one study,<ref name="pmid2149286" /> but not in another.<ref name="pmid2147128"/> 4-Hydroxy-''N''-desmethyltoremifene has also been found to be strongly antiestrogenic ''in vitro''.<ref name="pmid2147128" /> The metabolites of toremifene, particularly 4-hydroxytoremifene, may contribute importantly to the clinical activity of the medication.<ref name="pmid11108432" /><ref name="pmid2149286" /><ref name="pmid2147128" /> On the other hand, some authorities consider toremifene not to be a [[prodrug]].<ref name="pmid24439786">{{cite journal | vauthors = Vogel CL, Johnston MA, Capers C, Braccia D | title = Toremifene for breast cancer: a review of 20 years of data | journal = Clin Breast Cancer | volume = 14 | issue = 1 | pages = 1–9 | date = February 2014 | pmid = 24439786 | doi = 10.1016/j.clbc.2013.10.014 | doi-access = free }}</ref>

Toremifene is very similar to [[tamoxifen]] and shares most of its properties.<ref name="MillerIngle2002" /><ref name="MorrowJordan2003" /><ref name="ScholarlyEditions2013" /><ref name="RosenthalBurchum2017" /> There are some indications that toremifene may be safer than tamoxifen as it is not a [[wikt:hepatocarcinogen|hepatocarcinogen]] in animals and may have less potential for [[genotoxicity]].<ref name="MillerIngle2002" /><ref name="ChabnerLongo2011" /> However, clinical studies have found no significant differences between toremifene and tamoxifen, including in terms of [[effectiveness]], [[tolerability]], and [[drug safety|safety]], and hence the clinical use of toremifene has been somewhat limited.<ref name="MillerIngle2002" /><ref name="ChabnerLongo2011" /> Toremifene is thought to have about one-third of the [[potency (pharmacology)|potency]] of tamoxifen; i.e., 60&nbsp;mg toremifene is roughly equivalent to 20&nbsp;mg tamoxifen in the treatment of breast cancer.<ref name="pmid9647865">{{cite journal | vauthors = MacGregor JI, Jordan VC | title = Basic guide to the mechanisms of antiestrogen action | journal = Pharmacol. Rev. | volume = 50 | issue = 2 | pages = 151–96 | date = June 1998 | pmid = 9647865 | url = http://pharmrev.aspetjournals.org/content/50/2/151.short}}</ref>

Toremifene has been found to have [[antigonadotropic]] effects in postmenopausal women,<ref name="pmid14692654">{{cite journal | vauthors = Ellmén J, Hakulinen P, Partanen A, Hayes DF | title = Estrogenic effects of toremifene and tamoxifen in postmenopausal breast cancer patients | journal = Breast Cancer Res. Treat. | volume = 82 | issue = 2 | pages = 103–11 | date = November 2003 | pmid = 14692654 | doi = 10.1023/B:BREA.0000003957.54851.11 | url =https://deepblue.lib.umich.edu/bitstream/2027.42/44217/1/10549_2004_Article_5150739.pdf | hdl = 2027.42/44217 | s2cid = 207694212 | hdl-access = free }}</ref> [[progonadotropic]] effects in men,<ref name="pmid18692782">{{cite journal | vauthors = Tsourdi E, Kourtis A, Farmakiotis D, Katsikis I, Salmas M, Panidis D | title = The effect of selective estrogen receptor modulator administration on the hypothalamic-pituitary-testicular axis in men with idiopathic oligozoospermia | journal = Fertil. Steril. | volume = 91 | issue = 4 Suppl | pages = 1427–30 | date = April 2009 | pmid = 18692782 | doi = 10.1016/j.fertnstert.2008.06.002 | doi-access = free }}</ref> to increase [[sex hormone-binding globulin]] levels,<ref name="pmid14692654" /> and to decrease [[insulin-like growth factor 1]] levels by about 20% in postmenopausal women and men.<ref name="pmid29383334">{{cite journal | vauthors = Roelfsema F, Yang RJ, Takahashi PY, Erickson D, Bowers CY, Veldhuis JD | title = Effects of Toremifene, a Selective Estrogen Receptor Modulator, on Spontaneous and Stimulated GH Secretion, IGF-I, and IGF-Binding Proteins in Healthy Elderly Subjects | journal = Journal of the Endocrine Society| volume = 2 | issue = 2 | pages = 154–165 | date = February 2018 | pmid = 29383334 | pmc = 5789038 | doi = 10.1210/js.2017-00457 }}</ref>

In addition to its activity as a SERM, 4-hydroxytoremifene is an antagonist of the [[estrogen-related receptor γ]] (ERRγ).<ref name="pmid16515477">{{cite journal | vauthors = Ariazi EA, Jordan VC | title = Estrogen-related receptors as emerging targets in cancer and metabolic disorders | journal = Curr Top Med Chem | volume = 6 | issue = 3 | pages = 203–15 | date = 2006 | pmid = 16515477 | doi = 10.2174/1568026610606030203 }}</ref>

===Pharmacokinetics===

====Absorption====
The [[bioavailability]] of toremifene has not been precisely determined but is known to be good and has been estimated to be approximately 100%.<ref name="pmid11108432" /><ref name="Jr.Lawrence2015" /> Levels of toremifene at [[steady state levels|steady state]] with a dosage of 60&nbsp;mg/day are 800 to 879&nbsp;ng/mL.<ref name="pmid11108432" /> Levels of ''N''-desmethyltoremifene at steady state with toremifene were 3,058&nbsp;ng/mL at 60&nbsp;mg/day, 5,942&nbsp;ng/mL at 200&nbsp;mg/day, and 11,913&nbsp;ng/mL at 400&nbsp;mg/day.<ref name="pmid11108432" /> Levels of 4-hydroxytoremifene at steady state with toremifene were 438&nbsp;ng/mL at 200&nbsp;mg/day and 889&nbsp;ng/mL at 400&nbsp;mg/day.<ref name="pmid11108432" /> Concentrations of toremifene increase linearly across a dose range of 10 to 680&nbsp;mg.<ref name="pmid22356442">{{cite journal | vauthors = Gennari L, Merlotti D, Stolakis K, Nuti R | title = Pharmacokinetic evaluation of toremifene and its clinical implications for the treatment of osteoporosis | journal = Expert Opin Drug Metab Toxicol | volume = 8 | issue = 4 | pages = 505–13 | date = April 2012 | pmid = 22356442 | doi = 10.1517/17425255.2012.665873 | s2cid = 19547631 }}</ref><ref name="pmid2142247">{{cite journal | vauthors = Anttila M, Valavaara R, Kivinen S, Mäenpää J | title = Pharmacokinetics of toremifene | journal = J Steroid Biochem | volume = 36 | issue = 3 | pages = 249–52 | date = June 1990 | pmid = 2142247 | doi = 10.1016/0022-4731(90)90019-o }}</ref>

====Distribution====
Toremifene is 99.7% [[plasma protein binding|bound to plasma protein]]s, with 92% bound specifically to [[human serum albumin|albumin]], about 6% to [[beta-1 globulin|β<sub>1</sub> globulin]] fraction, and about 2% to a fraction between albumin and [[alpha-1 globulin|α<sub>1</sub> globulin]]s.<ref name="pmid22356442" /><ref name="pmid11108432">{{cite journal | vauthors = Taras TL, Wurz GT, Linares GR, DeGregorio MW | title = Clinical pharmacokinetics of toremifene | journal = Clin Pharmacokinet | volume = 39 | issue = 5 | pages = 327–34 | date = November 2000 | pmid = 11108432 | doi = 10.2165/00003088-200039050-00002 | s2cid = 26647296 }}</ref> The apparent [[volume of distribution]] of toremifene ranged from 457 to 958&nbsp;L.<ref name="pmid22356442" />

====Metabolism====
Toremifene is [[metabolism|metabolized]] in the [[liver]] primarily by [[CYP3A4]] and then undergoes secondary [[hydroxylation]].<ref name="Jr.Lawrence2015" /> The [[metabolite]]s of toremifene include ''N''-desmethyltoremifene, 4-hydroxytoremifene, and 4-hydroxy-''N''-desmethyltoremifene, among others.<ref name="pmid11108432" /><ref name="pmid2149286" /><ref name="Jr.Lawrence2015" /><ref name="BrennerStevens2017">{{cite book| vauthors = Brenner GM, Stevens C |title=Brenner and Stevens' Pharmacology E-Book|url=https://books.google.com/books?id=v3g4DwAAQBAJ&pg=PA394|date=28 September 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-39172-6|pages=394–}}</ref> [[Ospemifene]] (deaminohydroxytoremifene) is also a major metabolite of toremifene.<ref name="pmid11108432" /><ref name="Toremifene-Label"/>

====Elimination====
The [[elimination half-life]] of toremifene is 3 to 7&nbsp;days in healthy individuals.<ref name="pmid11108432" /> In people with [[impaired liver function]], the half-life is 11&nbsp;days.<ref name="pmid11108432" /> The elimination half-lives of the metabolites of toremifene are 5 to 21&nbsp;days for ''N''-desmethyltoremifene, 5&nbsp;days for 4-hydroxytoremifene, and 4&nbsp;days for ospemifene.<ref name="pmid11108432" /><ref name="Jr.Lawrence2015" /><ref name="Toremifene-Label"/> The long elimination half-lives of toremifene and its metabolites are thought to be due to [[enterohepatic recirculation]] and high plasma protein binding.<ref name="pmid11108432" /><ref name="RosenthalBurchum2017" /> Toremifene is [[elimination (pharmacology)|eliminated]] 70% in the [[feces]], as metabolites.<ref name="Jr.Lawrence2015" />

==Chemistry==
{{See also|List of selective estrogen receptor modulators|Triphenylethylene}}

Toremifene, also known as ''4-chlorotamoxifen'', is a [[chemical derivative|derivative]] of [[triphenylethylene]] and a close [[structural analog|analogue]] of [[tamoxifen]].<ref name="CanoAlsina2006">{{cite book| vauthors = Cano A, Calaf i Alsina J, Duenas-Diez JL |title=Selective Estrogen Receptor Modulators: A New Brand of Multitarget Drugs|url=https://books.google.com/books?id=heJDAAAAQBAJ&pg=PA52|date=22 September 2006|publisher=Springer Science & Business Media|isbn=978-3-540-34742-2|pages=52–}}</ref> It is also closely related to [[afimoxifene]] (4-hydroxytamoxifen) and [[ospemifene]] (deaminohydroxytoremifene).<ref name="Weber2015">{{cite book| vauthors = Weber GF |title=Molecular Therapies of Cancer|url=https://books.google.com/books?id=dhs_CgAAQBAJ&pg=PA304|date=22 July 2015|publisher=Springer|isbn=978-3-319-13278-5|pages=304–}}</ref><ref name="MaximovMcDaniel2013">{{cite book| vauthors = Maximov PY, McDaniel RE, Jordan VC |title=Tamoxifen: Pioneering Medicine in Breast Cancer |url= https://books.google.com/books?id=p-W5BAAAQBAJ&pg=PA170 |date=23 July 2013 |publisher=Springer Science & Business Media |isbn=978-3-0348-0664-0 |pages=170–}}</ref>

==History==
Toremifene was introduced in the [[United States]] in 1997.<ref name="SilvaZurrida2005">{{cite book| vauthors = Silva OE, Zurrida S |title=Breast Cancer: A Practical Guide|url=https://books.google.com/books?id=fqZqYKQLzfMC&pg=PA355|year=2005|publisher=Elsevier Health Sciences|isbn=0-7020-2744-8|pages=355–}}</ref><ref name="BidlackOmaye2000">{{cite book| vauthors = Bidlack WR, Omaye ST, Meskin MS, Topham DK |title=Phytochemicals as Bioactive Agents|url=https://books.google.com/books?id=-3DwAnmgyFYC&pg=PA26|date=16 March 2000|publisher=CRC Press|isbn=978-1-56676-788-0|pages=26–}}</ref> It was the first [[antiestrogen]] to be introduced in this country since tamoxifen in 1978.<ref name="DiSaiaCreasman2017">{{cite book| vauthors = DiSaia PJ, Creasman WT, Mannel RS, McMeekin DS, Mutch DG |title=Clinical Gynecologic Oncology E-Book|url=https://books.google.com/books?id=MkoQDgAAQBAJ&pg=PA124|date=4 February 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-44316-6|pages=124–}}</ref>

==Society and culture==

===Generic names===
''Toremifene'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}} and {{abbrlink|BAN|British Approved Name}}, while ''toremifene citrate'' is its {{abbrlink|USAN|United States Adopted Name}} and {{abbrlink|JAN|Japanese Accepted Name}} and ''torémifène'' is its {{abbrlink|DCF|Dénomination Commune Française}}.<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1222|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=1222–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA1048|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=1048–}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA277|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=277–}}</ref><ref name="Drugs.com">{{Cite news|url=https://www.drugs.com/international/toremifene.html|title=Toremifene - Drugs.com|work=Drugs.com|access-date=2018-02-08|language=en-US}}</ref>

===Brand names===
Toremifene is marketed almost exclusively under the brand name Fareston.<ref name="IndexNominum2000" /><ref name="Drugs.com" />

===Availability===
Toremifene is marketed widely throughout the world and is available in the [[United States]], the [[United Kingdom]], [[Ireland]], many other [[Europe]]an countries, [[South Africa]], [[Australia]], [[New Zealand]], and elsewhere throughout the world.<ref name="IndexNominum2000" /><ref name="Drugs.com" />

==Research==

Toremifene was also evaluated for prevention of [[prostate cancer]] and had the tentative brand name Acapodene.<ref>{{cite journal | vauthors = Price N, Sartor O, Hutson T, Mariani S | year = 2005 | title = Role of 5a-reductase inhibitors and selective estrogen receptor modulators as potential chemopreventive agents for prostate cancer | journal = Clin Prostate Cancer | volume = 3 | issue = 4| pages = 211–4 | pmid = 15882476 | doi = 10.1016/s1540-0352(11)70089-0 }}</ref>

In 2007 the pharmaceutical company [[Gtx inc|GTx, Inc]] was conducting two different phase 3 [[clinical trial]]s; First, a pivotal Phase clinical trial for the treatment of serious side effects of [[androgen deprivation therapy]] (ADT) (especially vertebral/spine fractures and [[hot flashes]], lipid profile, and [[gynecomastia]]) for advanced prostate cancer, and second, a pivotal Phase III clinical trial for the prevention of prostate cancer in high risk men with high grade [[prostatic intraepithelial neoplasia]], or PIN. Results of these trials are expected by first quarter of 2008<ref>{{cite press release
| title = GTx's Phase III Clinical Development of ACAPODENE on Course Following Planned Safety Review | publisher = GTx Inc. | date = 2007-07-12
| url = http://phx.corporate-ir.net/phoenix.zhtml?c=148196&p=irol-newsArticle&ID=1025420&highlight= | access-date = 2006-07-14 }}</ref>

An NDA for the first application (relief of prostate cancer ADT side effects) was submitted in Feb 2009,<ref>{{cite press release
| title = GTx Announces Toremifene 80 mg NDA Accepted for Review by FDA | url = http://phx.corporate-ir.net/phoenix.zhtml?c=148196&p=irol-newsArticle&ID=1257471&highlight= }}</ref> and in Oct 2009 the FDA said they would need more clinical data, e.g. another phase III trial.<ref>{{cite web |url=http://www.genengnews.com/gen-news-highlights/gtx-and-ipsen-end-prostate-cancer-collaboration-due-to-costs-of-fda-requested-phase-iii-study/81244761/ |title=GTx and Ipsen End Prostate Cancer Collaboration due to Costs of FDA-Requested Phase III Study |date=2 Mar 2011 }}</ref>

Ultimately, development was discontinued and toremifene was never marketed for complications associated with ADT or the treatment or prevention of prostate cancer.<ref name="AdisInsight">{{Cite web|url=http://adisinsight.springer.com/drugs/800004087|title=Toremifene - AdisInsight|website=adisinsight.springer.com|language=en|access-date=2018-02-08}}</ref>

Toremifene may be useful in the prevention of [[bicalutamide]]-induced gynecomastia.<ref name="pmid18062751">{{cite journal | vauthors = Sieber PR | title = Treatment of bicalutamide-induced breast events | journal = Expert Rev Anticancer Ther | volume = 7 | issue = 12 | pages = 1773–9 | date = December 2007 | pmid = 18062751 | doi = 10.1586/14737140.7.12.1773 | s2cid = 40410461 }}</ref>

=== Phase III Trial Results ===
A double-blind, placebo-controlled, randomized, 3 year clinical trial of toremifene was conducted using a sample of 1,260 men.  Subjects had a median age of 64 years and were diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN), which is considered premalignant, though Thompson and Leach feel a low grade PIN could also be deemed premalignant.<ref>Thompson Jr, I. M., and Leach, R.,  Prostate cancer and prostatic intraepithelial neoplasia: true, true, and unrelated? ''J Clin Oncol,'' 2013;31:515-6. https://ascopubs.org/doi/full/10.1200/JCO.2012.46.6151={{Dead link|date=April 2023 |bot=InternetArchiveBot |fix-attempted=yes }} Retrieved 31 July 2019</ref>

The sponsor, GTx, who designed and managed the study, found 34.7% of the placebo and 32.3% of the toremifene groups had cancer events. No distinction was found in [[Gleason score]]s of either group.<ref>Taneja, S. S., Morton, R., Barnette, G., Sieber, P., Hancock, M. L., and Steiner, M.,  Prostate cancer diagnosis among men with isolated high-grade intraepithelial neoplasia enrolled onto a 3-year prospective phase III clinical trial of oral toremifene ''J Clin Oncol,'' 2013;31:523-9. https://ascopubs.org/doi/abs/10.1200/JCO.2012.41.7634={{Dead link|date=April 2023 |bot=InternetArchiveBot |fix-attempted=yes }}  Retrieved 31 July 2019</ref>

Previous murine studies using transgenic adenocarcinoma of mouse prostate (TRAMP) mice showed toremifene prevented palpable tumors in 60% of the animals. This study used toremifene as an early prophylactic, which differentiates it from the phase III human studies.<ref>Raghow, S., Hooshdaran, M. Z., Katiyar, S., and Steiner, M. S., Toremifene prevents prostate cancer in the transgenic adenocarcinoma of mouse prostate model. ''Cancer Research'' 2002;62:1370-6. http://cancerres.aacrjournals.org/content/62/5/1370= Retrieved 31 July 2019</ref>

==References==
{{Reflist}}

==Further reading==
{{refbegin|30em}}
* {{cite journal | vauthors = Taras TL, Wurz GT, Linares GR, DeGregorio MW | title = Clinical pharmacokinetics of toremifene | journal = Clin Pharmacokinet | volume = 39 | issue = 5 | pages = 327–34 | year = 2000 | pmid = 11108432 | doi = 10.2165/00003088-200039050-00002 | s2cid = 26647296 }}
* {{cite journal | vauthors = Harvey HA, Kimura M, Hajba A | title = Toremifene: an evaluation of its safety profile | journal = Breast | volume = 15 | issue = 2 | pages = 142–57 | year = 2006 | pmid = 16289904 | doi = 10.1016/j.breast.2005.09.007 }}
* {{cite journal | vauthors = Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA | title = Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy | journal = Expert Opin Investig Drugs | volume = 15 | issue = 3 | pages = 293–305 | year = 2006 | pmid = 16503765 | doi = 10.1517/13543784.15.3.293 | s2cid = 29510508 }}
* {{cite journal | vauthors = Zhou WB, Ding Q, Chen L, Liu XA, Wang S | title = Toremifene is an effective and safe alternative to tamoxifen in adjuvant endocrine therapy for breast cancer: results of four randomized trials | journal = Breast Cancer Res. Treat. | volume = 128 | issue = 3 | pages = 625–31 | year = 2011 | pmid = 21553116 | doi = 10.1007/s10549-011-1556-5 | s2cid = 36985808 }}
* {{cite journal | vauthors = Gennari L, Merlotti D, Stolakis K, Nuti R | title = Pharmacokinetic evaluation of toremifene and its clinical implications for the treatment of osteoporosis | journal = Expert Opin Drug Metab Toxicol | volume = 8 | issue = 4 | pages = 505–13 | year = 2012 | pmid = 22356442 | doi = 10.1517/17425255.2012.665873 | s2cid = 19547631 }}
* {{cite journal | vauthors = Mao C, Yang ZY, He BF, Liu S, Zhou JH, Luo RC, Chen Q, Tang JL | title = Toremifene versus tamoxifen for advanced breast cancer | journal = Cochrane Database Syst Rev | issue = 7 | pages = CD008926 | year = 2012 | volume = 2021 | pmid = 22786516 | doi = 10.1002/14651858.CD008926.pub2 | pmc = 8407374 }}
* {{cite journal | vauthors = Vogel CL, Johnston MA, Capers C, Braccia D | title = Toremifene for breast cancer: a review of 20 years of data | journal = Clin. Breast Cancer | volume = 14 | issue = 1 | pages = 1–9 | year = 2014 | pmid = 24439786 | doi = 10.1016/j.clbc.2013.10.014 | doi-access = free }}
* {{cite journal | vauthors = Mustonen MV, Pyrhönen S, Kellokumpu-Lehtinen PL | title = Toremifene in the treatment of breast cancer | journal = World J Clin Oncol | volume = 5 | issue = 3 | pages = 393–405 | year = 2014 | pmid = 25114854 | pmc = 4127610 | doi = 10.5306/wjco.v5.i3.393 | doi-access = free }}
{{refend}}

==External links==
* [http://adisinsight.springer.com/drugs/800004087 Toremifene - AdisInsight]

{{Estrogens and antiestrogens}}
{{Estrogen receptor modulators}}

[[Category:Dimethylamino compounds]]
[[Category:Hepatotoxins]]
[[Category:Hormonal antineoplastic drugs]]
[[Category:Chloroethyl compounds]]
[[Category:Phenol ethers]]
[[Category:Prodrugs]]
[[Category:Progonadotropins]]
[[Category:Selective estrogen receptor modulators]]
[[Category:Triphenylethylenes]]